ABSTRACT This Orphan Drug Grant application is for a phase 1 clinical trial of talimogene laherparepvec (T-VEC), an oncolytic virus administered endoscopically, in the treatment of unresectable pancreatic cancer. Advanced pancreatic cancer is unfortunately nearly universally fatal with an estimated dismal median five-year survival of 6.8% for locally advanced disease and 2.8% for patients presenting with distant metastasis. We propose an investigator-initiated study in pancreatic cancer of T-VEC, a first in class oncolytic virus approved for the treatment of melanoma. No therapy prolonging survival more than several months is currently available to pancreatic cancer patients, and the failure of immunotherapy trials to enhance survival has been attributed to the unique immunosuppressive tumor micro-environment (TME) in pancreatic cancer. Oncolytic viruses, such as T-vec, may dramatically alter the TME through release of danger signals and activation of innate immune pathways. The proposed study has been approved by the FDA (IND#17248) and was submitted to the Columbia University IRB on 11/23/2016 (IRB#AAQ9966). T-VEC was previously tested in pancreatic cancer and showed good tolerability and evidence of activity with two minor responses and one stable disease out of 7 treated patients at the highest dose tested which was a log lower than the one used in melanoma. This study was abandoned before the MTD was reached for financial reasons. We now propose to complete this study and dose escalate to test T-VEC in pancreatic cancer at the same dose routinely used in melanoma. T-VEC kills tumor cells through direct oncolysis and also through secondary immune activation. Precise mechanisms of immunogenicity are largely unknown. Pre-clinical models show enhancement in local and systemic anti-tumor immunity while anecdotal human studies suggest alteration in the TME with increased CD8+T cell infiltration and decreased numbers of CD4+Foxp3+ regulatory T cells. Precise alteration in the TME is unknown and it has not been established whether T-VECinduces systemic immunity against cancer antigens. This study is a collaborative project between Columbia University and Johns Hopkins Medical Institute and the goals are to (1) define the MTD for T-VEC administered endoscopically in pancreatic cancer, (2) define changes induced in the local TME by T-VEC, specifically prevalence of T cell subsets, and (3) test whether the vaccine produces systemic antibody responses against pancreatic tumor antigens and compare these antibody responses with those that are induced by vaccination with GVAX, a GMCSF secreting irradiated pancreatic cancer cell line previously shown to alter the TME in pancreatic cancer. .